Hemochromatosis is a heterogeneous group of heritable disorders that increase the risk of developing iron overload due to increased dietary absorption of iron. Most hemochromatosis is due to mutation(s) in genes that alter the expression, structure, or ferroportin binding of hepcidin, a liver polypeptide that is the central regulator of iron absorption. Deleterious mutations that cause hemochromatosis include those of the HFE, HJV, TFR2, HAMP, and SLC40A1 genes. A rare mutation in the iron-responsive element of the FTH1 gene caused hemochromatosis due to decreased ferritin heavy-chain ferroxidase activity. Because mechanisms to excrete iron are limited, some persons with hemochromatosis develop iron overload and consequent target organ injury
4–10 per thousand (western European whites)
4–5 per thousand (non-Hispanic whites in United States)
1 in 200 (U.S. Vietnamese)
Rare, based on pathogenic mutations and cases discovered in population samples
Predominantly European whites; some Native Americans, U.S. Vietnamese, Hispanics, African Americans
Predominantly European whites; some Asians, Native Africans, African Americans, Japanese, Pacific Islanders
Male-to-female ratios in HFE hemochromatosis diagnosed in medical care:
Hemochromatosis genotype: 1:1
Elevated serum iron measures: 1.3:1
Elevated hepatic transaminase levels: 2:1
Diabetes mellitus: 4:1
Primary liver cancer: 5:1
Severe iron overload typically occurs in subjects 40–60 years old but is rare before age 30 years
Severe iron overload is common in children, adolescents, or young adults with HJV, TFR2, or “gain-of-function” SLC40A1 hemochromatosis
Normal in treated patients without cardiomyopathy, cirrhosis, or diabetes mellitus, and in individuals who do not develop iron overload
Mortality rate in U.S. Adults:
Barton JC et al. Genet Test 2007;11:269–275
Beutler E, Felitti VJ. Arch Intern Med 2002;162:1196–1197
Witte DL et al. Clin Chim Acta 1996;245:139–200
Yang Q et al. Ann Intern Med 1998;129:946–953
Etiology and Classification
Etiology and Classification
|Frequency ||Transmission ||Penetrance ||Ethnicity ||Presentation✫ ||Clinical Presentations |
|Hereditary Hemochromatosis Type: Classic Hereditary (HFE) Hemochromatosis |
|Common ||AR (C282Y) ||Low—Iron overload in <1% of heterozygotes ||European whites (90% have HFE C282Y) ||Second to fifth decades || |
Progressive iron overload
Joint and muscle pain
|AR (H63D, S65C, E168X) ||— || |
|AR (IVS5+1 G/A) || ||Vietnamese || |
|Hereditary Hemochromatosis Type 2A: Hemojuvelin (HJV) Hemochromatosis (Juvenile Hemochromatosis) |
|Uncommon ||AR ||High ||European whites ||First or second decades || |
Liver fibrosis or cirrhosis
Fatigue (older patients)
Diabetes mellitus (older patients)
With prolonged hypogonadism:
|Hereditary Hemochromatosis Type 2B: Hepcidin (HAMP) Hemochromatosis |
|Rare ||AR or digenic HAMP/HFE || ||European whites ||First or second decades || |
|Hereditary Hemochromatosis Type 3: Alternate Transferrin Receptor 2 (TFR2) Hemochromatosis |
|Rare ||AR ||<100% ||Italian and Japanese kinships ||Second or third ...|
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